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dc.contributor.author
Taylor, Gabrielle
dc.contributor.author
Frommherz, Yannick
dc.contributor.author
Katikaridis, Panagiotis
dc.contributor.author
Layer, Dominik
dc.contributor.author
Sinning, Irmgard
dc.contributor.author
Carroni, Marta
dc.contributor.author
Weber-Ban, Eilika
dc.contributor.author
Mogk, Axel
dc.date.accessioned
2022-08-04T06:49:04Z
dc.date.available
2022-08-01T04:42:17Z
dc.date.available
2022-08-04T06:49:04Z
dc.date.issued
2022-08
dc.identifier.issn
0021-9258
dc.identifier.issn
1083-351X
dc.identifier.other
10.1016/j.jbc.2022.102202
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/561059
dc.identifier.doi
10.3929/ethz-b-000561059
dc.description.abstract
The ring-forming AAA+ hexamer ClpC1 associates with the peptidase ClpP1P2 to form a central ATP-driven protease in Mycobacterium tuberculosis (Mtb). ClpC1 is essential for Mtb viability and has been identified as the target of antibacterial peptides like CyclomarinA (CymA) that exhibit strong toxicity toward Mtb. The mechanistic actions of these drugs are poorly understood. Here, we dissected how ClpC1 activity is controlled and how this control is deregulated by CymA. We show that ClpC1 exists in diverse activity states correlating with its assembly. The basal activity of ClpC1 is low, as it predominantly exists in an inactive nonhexameric resting state. We show that CymA stimulates ClpC1 activity by promoting formation of supercomplexes composed of multiple ClpC1 hexameric rings, enhancing ClpC1–ClpP1P2 degradation activity toward various substrates. Both the ClpC1 resting state and the CymA-induced alternative assembly state rely on interactions between the ClpC1 coiled-coil middle domains (MDs). Accordingly, we found that mutation of the conserved aromatic F444 residue located at the MD tip blocks MD interactions and prevents assembly into higher order complexes, thereby leading to constitutive ClpC1 hexamer formation. We demonstrate that this assembly state exhibits the highest ATPase and proteolytic activities, yet its heterologous expression in Escherichia coli is toxic, indicating that the formation of such a state must be tightly controlled. Taken together, these findings define the basis of control of ClpC1 activity and show how ClpC1 overactivation by an antibacterial drug generates toxicity.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
American Society for Biochemistry and Molecular Biology
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
ATPase Associated with diverse cellular Activities
en_US
dc.subject
antibiotic action
en_US
dc.subject
protein degradation
en_US
dc.subject
protease
en_US
dc.subject
proteostasis
en_US
dc.subject
ClpC
en_US
dc.subject
CyclomarinA
en_US
dc.title
Antibacterial peptide CyclomarinA creates toxicity by deregulating the Mycobacterium tuberculosis ClpC1–ClpP1P2 protease
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
ethz.journal.title
Journal of Biological Chemistry
ethz.journal.volume
298
en_US
ethz.journal.issue
8
en_US
ethz.journal.abbreviated
J Biol Chem
ethz.pages.start
102202
en_US
ethz.size
12 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.grant
Clp-dependent degradation in Mycobacterium tuberculosis: substrate profiles and adaptors
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Bethesda, MD
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02521 - Inst. f. Molekularbiologie u. Biophysik / Inst. Molecular Biology and Biophysics::08811 - Weber-Ban, Eilika (Tit.-Prof.)
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02521 - Inst. f. Molekularbiologie u. Biophysik / Inst. Molecular Biology and Biophysics::08811 - Weber-Ban, Eilika (Tit.-Prof.)
ethz.grant.agreementno
ETH-40 16-1
ethz.grant.fundername
ETHZ
ethz.grant.funderDoi
10.13039/501100003006
ethz.grant.program
ETH Grants
ethz.date.deposited
2022-08-01T04:42:28Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2022-08-04T06:49:11Z
ethz.rosetta.lastUpdated
2023-02-07T05:02:20Z
ethz.rosetta.versionExported
true
ethz.COinS
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